Summary Somatic stem cells (SCs) ensure homeostasis of high-turnover tissues by adjusting their proliferative activity in response to a wide range of damage and stress signals. To guarantee efficient regeneration while also preserving the size of the SC population during regenerative episodes, SC division modes can dynamically shift between symmetrically preserving divisions, symmetrically depleting divisions, and asymmetric divisions. Such a dynamic system allows rapid responses of the tissue to changing environmental conditions, by, for example, scaling the number of SCs according to the size of the tissue. The regulatory mechanisms that allow such dynamic responses of SCs to environmental conditions remain poorly understood. The applicant proposes a project that will explore the control of intestinal stem cells (ISCs) of the Drosophila gut, and is designed to specifically address how different ISC division modes are regulated in response to nutrient and stress signals. Based on preliminary studies, the applicant hypothesizes that oscillations in the intracellular concentration of Ca2+ are influenced by stress and nutrient signals and that the cytosolic Ca2+ concentration serves as an integrating signal to elicit dynamic responses of ISCs to changing environmental conditions. To test this hypothesis, the applicant proposes studies that take advantage of the genetic accessibility of Drosophila ISCs and will combine live imaging and transcriptome analysis to probe ISC responses to genetic and environmental perturbations. Specifically, the work will (i) explore the control of asymmetric and symmetric ISC divisions in response to nutrients and stress, (ii) test whether a signaling pathway regulating the Ca2+- responsive transcription factor CRTC integrates stress and dietary signals to control ISC activity, and (iii) assess whether ISCs are regulated by cooperative regulation of gene expression by CRTC and other signal-responsive transcription factors. The Drosophila ISC system has provided rich insight into stem cell regulation and the maintenance of tissue homeostasis. The regulatory processes in this system are evolutionarily conserved. Understanding the role of Ca2+ signaling in ISCs in the context of adaptive tissue growth, homeostatic regeneration, and epithelial stress responses is thus likely to provide significant new leads for possible therapies of human diseases, including intestinal cancers and inflammatory diseases.